HU211660A9 - Megestrol acetate formulation - Google Patents

Description

The present invention relates to pharmaceutical compositions containing megestrol acetate. Megestrol acetate is a generic name of 17-a-acyloxy-6-methyl-pregna4,6-diene, marketed under the name Megace by the Bristol-Myers Squibb Corporation under the name Megace.

Kirk et al., U.S. Pat. U.S. Patent 3,356,673 discloses a megestrol acetate tablet formulation containing lactose, magnesium stearate, and starch. Kirk et al. Also disclose that liquid formulations of megestrol acetate may be administered in the form of solutions, emulsions, suspensions, syrups and elixirs, but without providing details on the composition of such formulations.

Petrow et al., U.S. Pat. U.S. Patent No. 4,396,615 discloses a method of treating androgenic hormone disorders by administering 6-methylene-progesterone derivatives with megestrol acetate, but does not disclose what constitutes a megestrol acetate preparation.

Greaney et al., U.S. Pat. U.S. Pat. No. 4,370,321 discloses adjunctive therapy using megestrol acetate to treat breast cancer. Specifically, the type or composition of megestrol acetate formulation is not described.

Labrie a U.S.Pat. U.S. Patent No. 4,666,885 discloses combination therapy for the administration of luteinising hormones in combination with an anti-androgen, such as megestrol acetate, for the treatment of female breast cancer. Specifically, U.S. Patent No. 855, p. 58-61, p. It is contemplated that the anti-androgens be formulated into tablets or capsules for oral administration with conventional pharmaceutical excipients (e.g., spray-dried lactose and magnesium stearate).

Labrie U.S.Pat. U.S. Patent No. 4,760,053 relates to the treatment of sex steroid dependent cancers with combination therapy comprising the use of megestrol acetate but without disclosing the type or composition of the medicament used in the treatment.

Labrie U.S.Pat. U.S. Patent No. 4,775,661 relates to combination therapy for the treatment of female breast cancer, in which megestrol acetate is disclosed as a suitable steroid anti-androgen. It is further stated that megestrol acetate may be mixed with the active ingredient as excipients such as polyethylene glycol and may contain flavoring agents which can be incorporated into tablets or dragees.

J. H. Von Roenn et al., Annals of Intermediate Medicine, 109: 840-841 (1988) describe the use of megestrol acetate for the treatment of cachexia associated with human immunodeficiency virus infection (HIV). The dose of megestrol acetate is included, but not the type or composition of the formulation.

Currently, megestrol acetate is available as a tablet for therapeutic purposes. As described above, there is a perceptible lack of description of megestrol acetate pharmaceutical formulations other than tablets or capsules.

In view of the widespread use of megestrol acetate in clinical medicine, it would be desirable to provide a liquid pharmaceutical dosage form in cases where the patient is unable to swallow tablets or capsules, or when a large dose requires the administration of a relatively large number of tablets.

Therefore, one object of the present invention is the oral liquid dosage form of megestrol acetate.

Another object of the present invention is the oral liquid dosage form of megestrol acetate in suspension form.

The present invention also relates to an oral liquid dosage form of megestrol acetate in the form of a flocculated suspension.

The present invention also provides a megestrol acetate pharmaceutical formulation in the form of a flocculated suspension which does not deflocculate during the shelf life of the product.

The present invention also relates to the oral liquid dosage form of megestrol acetate in an aqueous dispersion which remains rapidly dispersible over a shelf life of at least two years, thereby providing a uniform dosage of megestrol acetate.

In accordance with the invention, the oral megestrolacetate pharmaceutical composition comprises micronized megestrolacetate in combination with polysorbate and polyethylene glycol, buffered, and sweeteners and flavoring agents are added for flavoring.

Other objects and advantages of the invention will be apparent from the following description and the appended claims.

A preferred embodiment of the present invention is an oral pharmaceutical composition comprising micronized megestrol acetate at a concentration of 15-150 mg / ml in combination with a polysorbate at a concentration of 0.005 to 0.015% w / v and a polyethylene glycol greater than 5% w / v, which composition forms a stable flocculated suspension in water. In a preferred embodiment of the invention, micronized megestrol acetate is 15-150 mg / ml, preferably

It provides an oral pharmaceutical composition containing 20-120 mg / ml and most preferably 40 mg / ml.

A suspension is a specific class of dispersion having an inner (suspended) phase made of a substantially insoluble but uniformly dispersible particulate material and an external phase containing a suspending medium or dispersant. In the most preferred composition of the invention, the internal phase comprises micronized megestrol acetate having an average particle diameter of 3 to 10 µm; and the outer phase consists essentially of pure water plus polysorbate 80, polyethylene glycol 1450, xanthan gum, sodium benzoate, citric acid, sucrose and flavoring agents.

The flocculated suspension contains a loose particulate aggregate (flake) in which the discrete particles are held together by a network structure. The flake, referred to as "stable flake", is usually a different amount of liquid medium

EN 211 660 A9 or dispersant is entrapped within the web and tends to aggregate in a weak aggregate.

The flocculated suspensions do not condense on standing and are easily dispersed by shaking. Formulation of a flocculated suspension generally requires the setting of a surfactant, wetting agent, protective colloid / suspending agent to obtain a stable flake that is resistant to deflocculation or agglomeration and thereby to compaction. Preservatives, buffers, sweeteners and flavoring agents are also used. The selection of excipients for pharmaceutical formulations is critical since relatively small changes can affect the properties of a stable flocculated suspension formulation.

Megestrol acetate, a hydrophobic solid, is not readily wettable with water and has a relatively high surface tension, which is emphasized by the entrapped air absorbed on the surface of the particle. Therefore, a surfactant and a wetting agent are required to obtain a suspension and maintain physical stability.

The flocculated megestrol acetate suspension of the invention requires micronized megestrol acetate having 90% by weight of the particles less than 20 µm and an average particle diameter of 3.0 to 10 µm, wherein the micronized particles are surfactant or wetting agent. e. g., polysorbate 80 and polyethylene glycol 1450 are dispersed in water, which are present to reduce the interfacial tension between the particle, the entrapped gas and the water. The amount of surfactant or wetting agent is particularly critical when creating a stable flake. R.A. According to Nash (Pharmaceutical Suspensions, Dosage Forms, Marcel Decker, New York, Chapter 5, page 181), the usual surfactant concentration ranges from 0.05 w / v% to 0.5 w / v% depends on the solids content to be included in the suspension. Table 1, which lists some currently available steroid suspensions (1989 Physicians Desk Reference, 43rd edition), provides examples of such suspensions and the concentration of polysorbate 80 surfactant.

Table 1

In steroid suspensions, the Physicians Desk

Reference, 43rd Edition,% Polysorbate 80 Concentration

steroid Steroid Conc. mg / ml Polysorbate 80 w / v% Aristocort Forte 40 0.2 Aristospan 20 0.4 5 0.2 Cortisol acetate 25-50 0.4 Decadron-LA 8 0,075 Depo-Provers 100 0.184 T. B., Hydeltre. 20 0.1 Hidrokorton acetate 25-50 0.4 Kenalog-40 40 0.04

Megestrol acetate suspensions prepared with the above polysorbate concentrations are unstable when deflocculated and condensed.

For the purpose of providing an instant, stable, flocculated megestrol acetate suspension, the concentration of polysorbate is about 0.02 w / v% or less, preferably 0.005 w / v% to 0.015 w / v%, and most preferably 0.01 w / v% must be. At concentrations of 0.025 w / v% polysorbate 80, significant deflocculation and compaction occurs. Polysorbate concentrations of 0.0050.01 w / v% or less yield a physically stable product, but at these low concentrations it becomes more difficult to moisten micronized megestrol acetate. Surfactants having properties similar to polysorbate 80 may also be used. In this regard, polysorbate 85 provides acceptable wetting properties. Other surfactants that may be used include polysorbate 20,40,60 and 65.

The wettability and suspension of micronized megestrol acetate is improved using a hydrophilic polymer. In this regard, the preferred hydrophilic polymer for preparing the megestrol acetate suspension of the present invention is polyethylene glycol (PEG) 1450 of between 5% w / v and 30% w / v, preferably between 12% w / v and 24% w / v and most preferably 20% w / v % concentration. The concentration of 30 w / v% PEG 1450 causes some handling problems due to the higher viscosity of the suspension but otherwise gives a suspension with acceptable physical properties. Suspensions made with concentrations of less than 8% PEG 1450 require additional efforts to moisten the drug, and it is not desirable for a small percentage of the drug to remain in a dry state containing air and then floating on the surface of the liquid. Polyethylene glycol 3350 at 3 w / v% is less effective in producing a fully wetted suspension than PEG 1450. Other grades of PEG having an average molecular weight of about 400 to about 4000 can also be used at preferred concentrations. PEG 1450 is particularly preferred because higher molecular weights result in high viscosity and low molecular weights degrade the taste.

The xanthan gum is preferably used as a suspending agent in an amount of about 0.2% w / v. The use of a suspending agent keeps the megestrol acetate particles uniformly suspended for a longer period of time during the administration period, thus allowing for uniform dosing. Xanthan gum is an instant high viscosity high molecular weight polysaccharide with thixotropic properties. In this regard, xanthan gum provides the most useful and elegant dosage form at concentrations of 0.1 to 0.3 w / v, and is preferred, most preferably at 0.2 w / v.

Conventional preservatives, buffers, sweeteners and flavoring agents are used. The following are preferred in this respect:

Sodium benzoate preservative 0.2 w / v,

Citric acid buffer and sodium citrate 0.244 and 0.015 w / v, respectively.

HU 211 660 A9

Sucrose sweetener 5 w / v%,

Green lemon aroma 0.91 v / M.

Example 1

Megestrol acetate preparation

A green lemon flavored oral suspension containing 40 mg / ml megestrol acetate has the following composition.

Example 2

Megestml acetate preparation

A green lemon flavored oral suspension containing 120 mg / ml megestrol acetate has the following composition.

Table 2

Megestrol acetate preparation

component Volume per ml wv% Micronized megestrol acetate 40 mg 4 polyethylene glycol 1450 200 mg 20 Polysorbate 80 0.1 mg 0.01 Xanthan Rubber TF 2.0 mg 0.2 Sodium benzoate 2.0 mg 0.2 Citric acid 2.44 mg 0,244 Sodium citrate 0.15 mg 0,015 saccharose 50.0 mg 5.0 N & A Green Lemon Flavor # 400639 0.91 0.091 Cleaned water q.s.1.0 ml

Table 3

Megestrol acetate preparation

component Volume per ml w / v% Micronized me gestrol acetate 120 mg 12 polyethylene glycol 1450 200 mg 20 Polysorbate 80 0.1 mg 0.01 Xanthan Rubber TF 2.0 mg 0.2 Sodium benzoate 2.0 mg 0.2 Citric acid 2.44 mg 0,244 Sodium citrate 0.15 mg 0,015 saccharose 50.0 mg 5.0 N & A Green Lemon Flavor # 400639 0.91 0.091 Cleaned water q.s.1.0 ml

Using the proportions of the ingredients, the megestrol acetate suspension was prepared as follows. About 90% of the PEG is melted (heated) and mixed with an equivalent weight of water and polysorbate 80 to form a solution. The solution is cooled to room temperature and micronized megestrol acetate is added and dispersed using a Lightin mixer with a high shear blade such as a Jiffy, Cowles or Hockmeyer blade. The xanthan gum is dispersed separately in about 10% of the molten PEG, and this gum slurry is then added to water to achieve a uniform hydration of the gum. The citrates, sucrose, sodium benzoate and aroma are then added to the gum dispersion and the gum slurry passed through a sieve. The rubber dispersion and the megestrol acetate dispersion are then mixed and mixed to form a uniform oral suspension. The whole suspension is then passed through a colloidal mill or homogenizer to obtain an oral suspension containing 40 mg / ml megestrol acetate. Suspensions containing megestrol acetate 75 to 200 mg / ml were prepared in a similar manner.

Example 3

suspension stability

One of the main criteria for assessing the acceptability of a suspension is the tendency of the suspension to flocculate. Generally, the greater the flocculation, the better the redispersibility. A common method for evaluating this is to measure sedimentation height. This is a useful approach to determine the physical stability of megestrol acetate suspension systems. Basically, the method involves determining sedimentation rates of the flocculated suspension by periodically measuring sedimentation height using a volumetric graduated cylinder without disturbing the system.

In Table 4, enter the sedimentation height as a percentage of the total suspension height

80 different concentrations of polysorbate in the formulations of Examples 1 and 2.

Table 4

Sedimentation height in% of total height

PS 80 concentration w / v% Time (weeks) 0 4 15 0,005 100 91 68 0.01 100 90 70 0.02 100 94 25 0.03 100 91 29

Obviously, the relative flocculations of the megestrol acetate suspension at concentrations of 0.005 and 0.01 w / v are significantly better than those found at PS80 concentrations of 0.02 w / v or more.

HU 211 660 A9

Example 4

Stability of PEG 1450 suspension

In the formulations of Examples 1 and 2, PEG

1450 concentrations vary from 5 w / v% to 20 w / v%. Periodic sedimentation heights are given in Table 5.

Table 5

Sedimentation height in% of total height

PEG 1450 concentration w / v% Time (weeks) 0 4 15 20 100 77 52 15 100 85 57 10 100 - 59 8 100 - 59 6 100 - - 5 100 - -

Poor wetting of the particles and entrapped air are indicated by sedimented and supernatant particles, including clear liquid.

Example 5

Suspension stability of polysorbate 80

In the formulations of Examples 1 and 2, PS80 concentrations range from 0.005 w / v% to 0.025 w / v% without the addition of xanthan gum suspending agent. Periodic sedimentation heights are given in Table 6.

Table 6

Sedimentation height in% of total height

Polysorbate 80 w / v% 0,005 0.01 0,015 0.02 0,025 0 days 100 100 100 100 100 One day 55 51 44 44 45 2 days 51 48 41 39 16 3 days 49 45 41 39 14 6 days 48 45 41 38 14 36 days 46 44 39 35 13 Supernatant appearance at day 36 Clean Clean Turbid Opalescent Opalescent

This example confirms the longer term results of Example 3 that, while flocculation at all concentrations of PS80 tested, concentrations ranging from 0.005 w / v% to about 0.015 w / v% provide flocculated suspensions of excellent stability.

Claims (10)

PATENT CLAIMS CLAIMS 1. An oral pharmaceutical composition containing micronized megestrol acetate in a concentration of 15-150 mg / ml in combination with polysorbate 0.005-0.015% w / v and polyethylene glycol greater than 5% w / v to form a stable flocculated suspension in water. The composition of claim 1, wherein the concentration of micronized megestrol acetate is 20120 mg / ml. The composition of claim 1, wherein the concentration of micronized megestrol acetate is 40 mg / ml. The composition of claim 1, wherein polysorbate 80 is used. The composition of claim 1, wherein the concentration of polyethylene glycol is between 5 and 30% w / v. The composition of claim 1, wherein the polyethylene glycol is present in a concentration of 12 to 24% w / v. The composition of claim 1, wherein the polyethylene glycol is present in a concentration of 20% w / v. The composition of claim 1, wherein the polysorbate is present at a concentration of 0.01% w / v. The composition of claim 1, comprising buffers, sweeteners and flavoring agents. 10. 4% megestrol acetate, 20% polyethylene glycol 1450, 0.01% polysorbate 80, 0.2% xanthan gum, 0.2% sodium benzoate, 0.244% citric acid, 0.015% sodium on a volume / volume basis. an oral pharmaceutical composition containing citrate, 5% sucrose, 0.091% green lemon aroma and partially purified water, which forms a stable flocculated suspension in water.